Novel 2-benzoyl benzaldehyde compounds

ABSTRACT

Novel 2(2-(1,3-diazacycloalk-2-enyl))benzophenone compounds and novel 1,3-diazacycloalkenyl(2,1-a)isoindole compounds having useful analgesic and psychostimulant properties are prepared inter alia by condensation of o-benzoylbenzaldehydes with aliphatic diamines.

United States Patent 1 1111 3,875,238 Metlesics et al. Apr. 1, 1975NOVEL Z-BENZOYL BENZALDEHYDE 3,408,366 l0/l968 White 260/591 COMPOUNDSInventors: Werner Metlesics, Clifton; Leo

Henryk Sternbach, Upper Montclair, both of NJ.

Assignee: Hoffman-La Roche, Nutley, NJ.

Filed: May 6, 1974 Appl. No.: 467,176

Related US. Application Data Division of Scr. No. 639,315, May 18, 1967,,which is a continuation-impart of Scr. No. 626,965, March 30,1967,21bandoncd.

US. Cl 260/591, 260/251 A, 260/251 R, 260/309.6, 260/326.5 B, 260/239BC,

Int. Cl. C07c 49/44 Field of Search 260/591 References Cited UNITEDSTATES PATENTS 7/l96l Roller et al 260/591 OTHER PUBLICATIONS Beilstein,Handbook of Organic Chem., 3rd Work, Vol. 7, part 3, p. 3827.

Primary E.\'aminerLeon Zitver Assistant Examiner-James H. ReamerAttorney, Agent, or Firm-Samuel L. Welt; Bernard S. Leon; William G.lsgro ABSTRACT 7 Claims, N0 Drawings NOVEL Z-BENZOYL BENZALDEHYDECOMPOUNDS RELATED APPLICATIONS This is a division of application Ser.No. 639,3]5, filed May 18. 1967, which in turn is a continuation-inpartof U.S. Pat. application Ser. No. 626,965. filed Mar. 30, I967 nowabandoned.

BRIEF SUMMARY OF THE INVENTION This invention relates to a novel classof 2[2-( 1,3- diazacycIoalk-2enyl)lbenzophenones and novel l 3diazacycloalkenyll2,l-a]isoindoles, novel processes and intermediatesfor the preparation of said novel products and derivatives thereof andto the use of said novel compounds as pharmaceuticals. Moreparticularly, the invention in its product aspect relates to novelcompounds of the formula wherein B represents an alkylene chain of 2 to4 carbon atoms in which one or more of the hydrogens can be replaced bylower alkyl; and R,, R R and R are each independently selected from thegroup consisting of hydrogen, halogen. lower alkyl, lower alkoxy.hydroxy and trifluoromethyl and pharmaceutically acceptable acidaddition salts thereof.

Compounds of formula I can undergo a prototropic shift to form compoundsof the formula B2 II wherein R,, R R R and B each have the same meaningas hereinabove.

The invention includes both tautomeric isomers as well as mixturesthereof. Tautomeric mixtures can be represented schematically as 1wherein R,, R R R and 3 each have the same H meaning as hereinabove.

DETAILED DESCRIPTION In one product aspect this application pertains tothe novel compounds of formulas I and II and derivatives thereof. Ofparticular interest are the compounds of formulas I and 11 wherein Brepresents the group R E .6 and R and R are each independently hydrogenor lower alkyl, i.e., compounds of the formulas N-CH-RS R N-CH-R H N-CHRR1 N-cH-R,

Re C

wherein R R R and R each have the same meaning as hereinabove; and R andR are each independently hydrogen or lower alkyl 5s and theirpharmaceutically acceptable acid addition salts and tautomeric mixtures.

Compounds of formulas I-a and II-a wherein R R R and R,; are eachhydrogen, i.e., compounds of the formulas H-C'H \N-CHZ N-? 2 n-cng RII-b wherein R and R each have the same meaning as hereinabove and theirpharmaceutically acceptable acid addition salts and tautomeric mixturesconstitute a preferred group.

In another product aspect this application pertains to the mixed ethersobtained from compounds of formula I] and lower alkanols, i.e.,compounds of the formula wherein R R R R and B each have the samemeaning as hereinabove; and R is lower alkyl.

In still another product aspect this application pertains to novelintermediates which will be more fully described with reference to theseveral processes for the preparation of compounds of formulas I and II.

In one of its process aspects this application pertains to thepreparation of compounds of formulas I, II and ll-d according to thefollowing reaction sequence.

ltf R2 R03 N R c? B H R2 2 O R 3 R3 4 I II- 4 C B R1 e 4 II-d wherein RR R R R and B each have the same meaning as hereinabove.

'The diol starting materials of formula V are known compounds or arereadily obtainable in analogy to the preparation of the known compounds.The diol starting materials can be readily converted to the dicarbonylintermediates of formula IV by oxidation techniques which are known perse such as, for example, using selenium dioxide and the like, as theoxidizing agent or by employing other oxidizing systems such as chromiumtrioxide in pyridine.

Treatment with" an oxidizing agent can be conveniently carried out in anorganic solvent such as, for example, dimethylformamide,dimethylsulfoxide; hydrocarbon solvents such as benzene, toluene;alkanols, e.g., the lower alkanols, methanol, ethanol, etc.; acetic acidand the like. The oxidation reaction is preferably carried out at anelevated temperature suitably at a temperature between about roomtemperature and about C.

The intermediates of formula IV are themselves novel compounds and thusalso constitute part of this invention. The intermediates of formula IVare readily condensed with diamines of the formula wherein B has thesame meaning as hereinabove by mixing the components or by reacting themin the presence of an organic solvent such as benzene, toluene; alcoholssuch as lower alkanols and the like. The condensation is convenientlycarried out at room temperature or above, preferably at a temperaturebetween about 20C. and 150C. Alternatively, the diamine reactant offormula XII can be employed as a salt thereof in which case the reactionis conducted by heating the mixture of reactants to a melt.

The reaction products, i.e., the compounds of formula Ill, can bereadily oxidized, for example, by treatment with an oxidizing agent suchas hydrogen peroxide or by exposure to gaseous oxygen at roomtemperature to give the peroxides of formula II-c which are readilyreduced to the corresponding end products. The oxidation is convenientlycarried out in an organic solvent such as alcohols, dimethylformamide,etc. at room temperature. Higher or lower temperatures, e.g.. betweenabout 20C. and 100C, can also be employed.

Since the peroxide intermediates readily undergo reduction, the reactionmixture obtained upon treatment of a compound of formula III with anoxidizing agent will ordinarily contain the end products along with theperoxide intermediate of formula II-c. Complete reduction of theperoxide can be accomplished without separating it from the reactionmixture and, in a preferred embodiment, the oxidation product issubmitted directly to treatment with a reducing agent. If desired,however, the peroxide intermediate of formula ll-c can be separated fromthe reaction mixture obtained upon treatment of a compound of formulaIII with an oxidizing agent by any of the usual techniques, e.g.,chromatographic separation, fractional crystallization, etc.

The reduction of the peroxide is conveniently carried out by employingany reducing agent conventionally used for the reduction of peroxidessuch as sodium sulfite, trialkylphosphite, etc. preferably in thepresence of an organic solvent such as an alcohol, e.g., methanol,ethanol, etc.; dimethylformamide and the like, or when using a salt ofthe peroxide, the reduction can. be carried out in an aqueous solvent,e.g., in an aqueous alcoholic solvent. The reduction is suitably carriedout at room temperature or above, preferably at a temperature betweenabout 20C. and lOC.

As noted above, the hydroxyl proton of a compound of formula II canundergo a prototropic shift to form the corresponding isomeric endproduct of formula I. In solution the product obtained upon oxidationand reduction of an intermediate of formula III will ordinarily be amixture of the tautomeric forms I and II. The relative amounts of theisomeric forms present is dependent upon such factors as the solventsystem employed, the pH of the medium and the particular product, i.e,the meaning of B, R,, R R and R, in formulas I and II. For example, in asolution of chloroform the product obtained upon oxidation and reductionof 2,3- dihydro-S-phenyl-SH-imidazol2,l-a]isoindole contains a mixtureof the isomers 2,3-dihydro-5-hydroxy-5-phenyl-SH-imidazol2,l-a]isoindole and 2-(2-benzoylphenyl)-2-imidazolinein a ratio of about 1:1. The acid addition salts isolated in theordinary manner from the reaction product of the'oxidation and reductionof 2,3- dihydro-S-phenyl-5H-imidazol 2, l -a]isoindole are ordinarilyobtained as structure I.

Compounds of formula II-d are prepared from compounds of formula II bytreating an acid addition salt, e.g., the hydrochloride, hydrobromide orthe like, of a formula II compound with a lower alkanol preferably at anelevated temperature. The etherification can be suitably carried outusing the lower alkanol as solvent or in the presence of an inertorganic solvent such as ether and the like and preferably at atemperature between about room temperature and the reflux temperature ofthe reaction mixture, i.e., up to about 150C.

The novel compounds of formula II-d as well as the intermediates offormulas II-c and III are obtained as racemates. It is intended toinclude in this invention all of the stereoisomeric forms whether theyare obtained as racemic mixtures or as the separated optically activeantipodes.

The intermediates of formulas III and II-c. are also 5 novel compoundswhich constitute part of this invention. Compounds of formula III are,in addition to being useful as intermediates in the preparation ofcompounds of formulas I and II, also useful as psychostimulant,anti-inflammatory and anti-pyretic agents.

Alternatively, the compounds of formulas III, II and I can be preparedaccording to the following reaction scheme:

R2 R2 OOH VII 1::

NH2-B-NH2 H 0 R- N-B-NH2 R N- 2 H VI VIII wherein R R R R and B eachhave the same meaning as hereinabove. l

According to one alternative synthesis outlined above the intermediatesof formula III are prepared by cyclization ofa phthalimidine of formulaVI. The cyclization of phthalimidine of formula VI to form anintermediate of formula III is readily accomplished by treatment with aLewis acid such as titanium chloride, boron trifluoride and the like.The oxidation and reduction of the formula ll intermediates to form thedesired end products is accomplished by the procedures described above.

The reaction with Lewis acid is preferably carried out in the presenceof an inert organic solvent, e.g., hydrocarbon solvents such as toluene,xylene and the like, and preferably at an elevated temperature suitablyat the reflux temperature of the solvent employed. A preferredtemperature range for the cyclization of the phthalimidines is atemperature between about 50C. to about 200C. The phthalimidineintermediates of formula VI are prepared by condensing a 3-phenylphthalide of formula Vll with a diamine of for mula XII. The3-phenylphthalides of formula VI! and the diamines of formula X employedas starting materials are known compounds or analogs of known compoundswhich are readily accessible in analogy to the known compounds.

The preparation of the formula VI intermediates is catalyzed by salts oforganic bases such as pyridine, trialkylamine, quinoline,ethylenediamine, etc., with acids such as an organic acid, a mineralacid, e.g., sulfuric acid, hydrohalic acid, phosphoric acid, perchloricacid, etc., or a Lewis acid such as zinc chloride, aluminum chloride.etc. Preferred catalysts for the reaction are the salts ofethylenediamine and pyridine such as pyridinium hydrochloride and thelike. It is preferred to carry out the reaction with an excess of theethylenediamine reactant as solvent. However, inert organic solventssuch as alcohols, e.g., methanol, ethanol, etc.; hydrocarbons. e.g.,benzene, toluene, etc.; ethers, e.g., tetrahydrofuran. dioxane, etc.,can also be employed. The reaction is carried out at an elevatedtemperature, preferably at a temperature above 100C. Especially suitabletemperatures for carrying out this reaction are temperatures betweenabout 180C. and about 250C.

The preparation of the phthalimidines of formula VI does not itselfconstitute part of this invention and is given here for the sake ofcompleteness only.

Alternatively, the intermediate of formula Ill can be prepared from theenylisoindolones of formula Vlll by reaction with an appropriatephenyl-organometallic derivative of the formula wherein R and R eachhave the same meaning as hereinabove; and Z is Li, MgBr, Mgl, MgCl orthe like.

corresponding diazacycloalk- The reaction with a phenyl-lithiumderivative of formula X] can be conveniently carried out in the presenceof an inert solvent at about room temperature. Higher or lowertemperatures suitably in the range of about 10C. to about C. can also beemployed. Suitable solvents that can be utilized are, for example, thehydrocarbons such as benzene, toluene, xylene, etc., ethers, and thelike or mixtures of such solvents.

The diazacycloalkenylisoindolone intermediates of formula VllI are alsonovel compounds and thus constitute a part of this invention. They arereadily prepared by the condensation of a phthalaldehydic acidderivative of formula IX with an alkylene diamine of formula XII. Thecondensation reaction is conveniently carried out in the presence of aninert organic solvent and preferably at an elevated temperature.Suitable temperatures for carrying out the condensation reaction aretemperatures between about 20C. and about 100C. or the boiling point ofthe reaction mixture. As solvent for the condensation there can besuitably employed any of the usual organic solvents such as alcohols,hydrocarbons, ethers, etc.

The phthalaldehydic acid derivatives of formula IX are known startingmaterials or analogs of known compounds readily obtained by knownprocesses.

In still another alternative process, the end products of formula I canbe obtained by oxidation of a lphenyl-2-aminoalkylisoindoline derivativeas outlined below:

R: on

B2 on L v Rl @f x R2 HX R3 Pt V-a i NHZ 4mm R1 CH2\ N-B-NHg R2 CHwherein B, R,, R R and R, are as defined hereinabove; and X is halogen,preferably chlorine, iodine or bromine or other similar leaving groupssuch as mesyloxy, tosyloxy and the like.

The oxidation is accomplished by treating with an oxidizing agent suchas gaseous oxygen or chemical oxidants as chromium trioxide in aceticacid and the like.

The reaction is preferably carried out in the presence of an organicsolvent such as, for example, hydrocarbon solvents, e.g., benzene,toluene or the like; alkanoie acids, e.g., acetic acid, propionic acid,etc.; ethers, alcohols and solvents such as dimethylformamide, etc. Thereaction can be suitably accomplished at room temperature or at anelevated temperature, preferably at a temperature between about 20C. andlC. The I-phenyl-2-aminoalkylisoindoline intermediates are prepared fromthe diols of formula V via a diester of formula V-a. The diesters areobtained by the usual techniques for esterification, e.g., treating thediol with one of the ordinary esterifying agents such as halo acid andhalides such as phosphorous halide, thionyl halide, tosyl halide, etc.The diester of formula V-a is in turn converted to the 1-phenyl-2-aminoalkylisoindoline intermediate of formula VI by condensing with adiamine of formula XII.

The reaction with diamine is conveniently carried out by adding thediester of formula V-a to the diamine at room temperature. Preferably,there is employed a large molar excess of diamine. The reaction can alsobe carried out at temperatures above or below room temperature, althoughfor practical reasons it is preferred to operate at a temperaturebetween about 0C. and 100C. The reaction is suitably carried out in thepresence of an organic solvent such as, for example, benzene, methylenechloride, ether, tetrahydrofuran and the like; or, in the case whereeither or both of the reactants are liquid under the conditions employedin the reaction, the reaction is conveniently carried out in the absenceof a solvent.

The preparation of the l-phenyl-2- aminoalkylisoindolines of formula VIdoes not constitute part of this invention and is given here for thesake of completeness only.

As used throughout this application the term lower alkyl denotesstraight and branched chain hydrocarbons containing 1 to 6 carbon atomssuch as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t.-butyl andthe like.'The term lower alkoxy denotes lower alkylether groups whereinthe alkyl group is as defined above. The term halogen as used hereinincludes all four halogens, i.e., chlorine, bromine, iodine and fluorme.

Suitable salts of the compounds of formula I are prepared from nontoxicorganic and inorganic acids. Suitable organic acids are, for example,maleic acid, fumaric acid, ascorbic acid, tartaric acid, salicylic acid,succinic acid, citric acid and the like. Suitable inorganic acids are,for example, the hydrohalic acids, e.g., hydrochloric acid andhydrobromic acid; sulfuric acid, sulfamic acid, phosphoric acid, etc.The acid addition salts are readily prepared by the usual techniques forthe preparation of acid addition salts which are readily apparent tothose skilled in the art.

As has been indicated hereinabove the novel end products of thisinvention, i.e., the compounds of formula I and their pharmaceuticallyacceptable acid addition salts and the compounds of formula lI-d andtheir pharmaceutically acceptable acid addition salts, are useful aspsychostimulants. When administered, for example, orally, to animalssuch as mice they produce a direct-acting stimulant effect of longduration in single doses in amounts ranging from 0.03 mg/kg to 50 mg/kg.By way of illustration the compound of Example l0,2-(2-benzoylphenyl)-2-imidazoline, which has an LD in mice of 200 mg/kgpo; mg/kg 5.0.; 77 mg/kg i.p.; and 37 mg/kg iv (Proc. Soc. Exprl. Biol.Med., Vol. 57, page 261 reversed the hypothermia induced by reserpine inmice at a dose of 10 mg/kg s.c. (Med. P/zarmacol. E.\'p., Vol. l2, pages226-232, 1965); prevented the ptosis induced by tetrabenazene in mice at0.06 mg/kg p.o. (Pletscher et al., Process. Drug Research, Vol. II, page417, I960); reversed the reserpine (10 mg/kg s.c.) induced sedation inmice by increasing their locomotor activity at doses of 25-50 mg/kg po(Med. Pharmacol. Exp, Vol. 12, pages 226-232, 1965); and potentiated theeffects of /3-(3,4- dihydroxyphenyl)-a-alanine (DOPA) in mice at a doseof 6.25 mg/kg i.p. (Arc. Exp. Path. and Pharm., Vol. I40, page 237). Thecompounds of this invention have psychostimulant effects qualitativelysimilar in many respects to those of imipramine and amphetamine whichare well-known for their therapeutic uses and properties. Among otherillustrative compounds of formulas I and II-d which have been similarlytested and found to be qualitatively similar to2-(2-benzoylphenyl)-2-imidazoline, there can be named by way ofexemplification the following:

5-(4-chlorophenyl)-2,3-dihydro-5-hydroxy-5H- imidazo[2, l -a]-isoindole;2,3-dihydro-5-hydroxy-5-(4-methoxyphenyl)-5H- imidazo[2,l-a]-isoindole;and 2,3-dihydro-5-methoxy-5-phenyl-5H-imidazo[2,l-

a]isoindole. The activity of the claimed compounds of formulas I andII-d first demonstrated by pharmacological evaluation in warm-bloodedanimals as indicated herein permits their use in therapy in the samegeneral manner as imipramine or amphetamine, which latter compoundsexhibit psychostimulant activity in the DOPA potentiation test at dosesof 10 mg/kg i.p. and 1.0 mg/kg i.p. respectively and in the ptosisprevention test at doses of 60 mg/kg and 7.5 mg/kg respectively. As afurther illustration of the psychostimulant activity of the compounds offormulas I and II-d, the compound of Example 21,2,3,4,5-tetrahydro-7-hydroxy-7-phenyl-7I-I- diazepino-[2,l-a]isoindole,which has an LD of 40 mg/kg i.v., prevented the ptosis induced bytetrabenazene at 0.4 mg/kg p.o.; reversed the hypothermia andhypometabolic effects induced by reserpine 10 mg/kg s.c.) in mice at 25mg/kg p.o.; and potentiated the effects of DOPA in mice at a dose of 7.5mg/kg i.p. The compounds of this invention thus demonstrate a pattern ofactivity associated with anti-depressants of known clinical efficacy andare similarly useful as psychostimulants in the treatment of depressedstates, for example, in cases of simple depression or in cases ofchronic nervous exhaustion.

In addition to their use as psychostimulants, the compounds of formulasI and Il-d are also useful as analgesic agents. By way of example,2-(2-benzoylphenyl)-2- imidazoline, when submitted to standardpharmacological tests for analgesic properties, exhibited markedactivity in the writhing test in mice at doses of 30.8 mg/kg p.o. and 5mg/kg s.c. and anti-pyretic activity in rats at doses of 6.25 to 50mg/kg p.o. The compound also showed potent anti-inflammatory activity inthe inflamed rat foot test at 6.25 mg/kg p.o. and anti-edema activity inthe Carrageenan anti-edema rat paw test at 6.25 mg/kg p.o. In theunanesthetized cat test for muscle relaxants the compound was active ata dose of 2.5 mg/kg p.o. Based on the foregoing pharmacological tests inanimals, the analgesic properties of the novel end products of thisinvention and particularly those of 2-(2-benzoylphenyl)-2-imidazolinecan be likened to the analgesic properties of phenylbutazone which iswell known for its therapeutic uses and properties. Compounds offormulas I and lI-d are also useful as anorexigenic agents owing totheir marked activity in the 4-hour anti-obesity test in rats whereincompounds of this class have demonstrated activity qualitatively similarto amphetamine. Compounds of this series have also demonstrated usefulcardiovascular properties. For example,2-(2-benzoylphenyl)-2-imidazoline in dogs at 4 mg/kg i.v. produced anincrease in blood pressure of mm. Hg after 2 minutes followed by gradualincrease to mm. Hg.

Compounds of formula I have also been found to be active as anti-fungalagents. For example, they have been found to be active in vitro inCandida albicans, Microsporum audouini and Tric/zoplzytonmentagrophyles. Accordingly, these compounds can be employed asanti-fungal agents in the treatment of pathogenic diseases caused bythese organisms. They can, for example, be employed in the treatment ofinfectious fungal diseases such as moniliasis and dermatomycoses. Forthe treatment of fungal infections the compounds of formula I can beemployed by applying a suitable composition containing about 0.1 mg. toabout 5 g. of active material over the site of the infection. Suitablecompositions are prepared by embodying a compound of formula I or apharmaceutically acceptable salt thereof in a conventional carriersuitable for topical administration.

The novel end products of this invention, i.e., the compounds offormulas l and II-d are mostly white crystalline odorless solids meltingat temperatures in the order of 200C. They have basic properties and canbe conveniently prepared in the form of their acid addition salts.Suitable salts are prepared as described hereinabove. The salts arecharacteristically white crystalline odorless solids soluble in waterand have good stability under ordinary conditions.

The compounds of formulas I and II-d, preferably in the form of theiracid addition salts can be formulated into preparations suitable foradministration by enteral or parenteral routes. They can be embodied inpharmaceutical unit dosage forms containing from about 0.5 mg. to aboutmg. of active materials, i.e., a compound of formulas I or II-d or asalt thereof. Parenteral formulations will ordinarily contain less ofthe active substance than compositions intended for enteral, e.g., oral,administration. For oral administration the products of this inventioncan be prepared as tablets, capsules and the like containing about 10 to50 mg. of active material. Formulations suitable for oral administrationmay be such as to provide either immediate, or in the alternative,sustained release of the active drug. In general, the formulations willbe prepared with pharmaceutically acceptable adjuvant materialscomprising from about 60 to about 98 per cent of the weight of thecompositions in oral dosage form.

For parenteral administration the compounds can be formulated with aliquid diluent, for example, distilled water, in the preparation of asuitable parenteral dosage form. The preferred parenteral dosage formwill contain from about 0.5 mg. to about 15 mg. of the active drug. Ingeneral, the compounds of thisinvention are formulated with conventionalinert adjuvants into dosage forms suitable for enteral or parenteraladministration following the conventional techniques and procedures ofthe prior art. Suitable dosage forms include tablets and capsules aswell as solutions, emulsions and suspensions. The inert adjuvants whichare suitable for use in preparing the various dosage forms includeliquids and solids inorganic or organic in nature such as water,gelatin, lactose, starch, magnesium stearate, talc, vegetable oils,gums, polyalkylene glycols, Vaseline. etc. Additionally, the compoundscan be used in combination with preservatives, stabilizers, wetting oremulsifying agents, salts for altering the osmotic pressure, buffers,etc. If desired, the compounds can be used also in admixture with othertherapeutically valuable substances. Specific embodiments showingillustrative formulations of an exemplary compound of formula I follow.

Tablet Formulation Per Tablet 2-(2-benzoylphenyl)-2-imidazoline l0.0 mg.Lactose 113.5 mg. Corn Starch 70.5 mg. Pregelatinized Corn Starch 8.0mg. Calcium Stearate 3.0 mg.

Total Weight 205.0 mg.

Procedure:

I. 2-(2-Benzoylphenyl)-2-imidazoline was mixed with the lactose, cornstarch, and pregelatinized corn starch in a suitable size mixer.

2. The mix was passed through a Fitzpatrick Comminuting Machine fittedwith a No. lA screen and with knives forward.

3. The mix was returned to the mixer and moistened with water to a thickpaste. The moist mass was passed through a No. 12 screen and the moistgranules were dried on paper-lined trays at 100F.

4. The dried granules were returned to the mixer, the calcium stearatewas added and mixed well.

5. The granules were compressed at a tablet weight of 200 mg., usingstandard concave punches having a diameter of 5/16 inch.

Suppository Formulation Per l.3 Gram Suppository2-(2-benzoylphenyl)-2-imidazoline 0.025 gram Wecobee M (E. F. DrewCompany 1.230 gram 522 Fifth Avenue New York, New York) Carnauba Wax0.045 gram Procedure:

1. The Wecobee M and the carnauba wax were melted in a suitable sizeglass-lined container (stainless steel may also be used), mixed well andcooled to 45C.

2. 2-(Z-Benzoylphenyl)-2-imidazoline, which had been reduced to a finepowder with no lumps, was added and stirred until completely anduniformly dispersed.

3. The mixture was poured into suppository molds to yield suppositorieshaving an individual weight of 1.3 grams.

4. The suppositories were cooled and removed from molds. They wereindividually wrapped in wax paper for packaging. (Foil may also beused.)

Capsule Formulation Per Capsule Z-(Z-benzoylphenyl)-2-imidazoline 25 mg.Lactose l58 mg. Corn Starch 37 mg. Talc 5 mg. Total Weight 255 mg.

Procedure:

1. 2-(2-Benzoylphenyl)-2-imidazoline was mixed with the lactose and cornstarch in a suitable mixer.

2. The mixture was further blended by passing through a FitzpatrickComminuting Machine with a No. lA screen with knives forward.

3. The blended powder was returned to the mixer, the talc added andblended thoroughly. The mixture was then filled into No. 4 hard shellgelatin capsules on a Parke Davis capsulating machine (any similar typemachine may be used).

Parenteral Formulation Per cc.

2-(2-benzoylphenyl)-2-imidazoline 2.5 mg. Tartaric Acid q.s. ad pH 3.0Phenol Anhydrous 4.5 mg. Water for injection. U.S.P. q.s. ad 1.0 cc.

The drug was prepared in duplex ampuls, one containing the dry drug andthe other containing the special diluent.

Dry Fill Ampul 5 cc.

2-( Z-benzoylphenyl )-2-imidazoline 25 mg.

Special Diluent 2 cc.

per ml.

Tartaric acid 16 mg. Water for injection q.s. to 1.0 ml.

In a suitable container under an atmosphere of nitrogen the tartaricacid was dissolved in part of the water for injection. The solution wasmade to volume, filtered through an 02 Selas candle filter and filledinto 2 cc. flint ampuls. The filling should be done under an atmosphereof nitrogen. The ampuls were sealed and sterilized at 212F. for 30minutes. The ampuls were then inspected and those that leaked orcontained fibers were discarded.

The drug in the preferred oral dosage form, i.e., tablets or capsulescontaining 10 to 25 mg. of active material, will be administered underordinary circumstances three or four times daily. The parenteralcomposition will be administered ordinarily one or two times daily.Effective dosages for the administration of compounds of this invention,i.e., the compounds of formulas l and lI-d, will, of course, depend inall instances upon the severity and individual characteristics of eachcase as determined by the prescribing practitioner. It will beunderstood that dosage forms containing larger and smaller quantities ofthe active drug ingredient are encompassed by the scope of thisinvention and that such dosage forms can be administered more or lessfrequently than indicated heretofore. It will be understood that dosageforms containing inert adjuvants in quantities which are greater or lessthan those indicated heretofore are also encompassed by this invention.

The invention will be more fully understood from the examples whichfollow. These examples are illustrative of the invention and are not tobe construed as limitative thereof. All melting points are in degreescentigrade. Decomposition melting points were taken in a Thomas Hooverapparatus in open capillaries. They may vary il0 depending on the rateof heating.

EXAMPLE 1 Preparation of 2-benzoylbenzaldehyde A mixture of 1 g. ofselenium dioxide and l g. of Z-hydroxymethylbenzhydrol in 5 ml. ofacetic acid was refluxed for 4- /2 hours. The solution was cooled,filtered from selenium and the filtrate was poured into ice water andmade alkaline with sodium hydroxide. Extraction with ether gave a yellowoil to which petroleum ether was added. White prisms were obtained whichmelted at 6467. Ultraviolet maximum (2- propanol) at 226/7 p. (e 15,750)and 251/2 p. (B= 18,500), inflexion at 294 ,u. (e 2600); infraredabsorption (Cl-lCl at 1665 cm and 1705 cm.

Anal. Calcd. for C H .,O- C. 79.98; H. 4.79 Found: C, 80.00; H. 4.68

EXAMPLE 2 Anal. Calcd. for C H Clo z C, 68.72; H, 3.71 Found: C. 69.12;H. 3.50

EXAMPLE 3 Preparation of Z-(p-anisoyl)-benzaldehyde A solution of 26 g.of 4-methoxy-2-hydroxymethylbenzhydrol in 140 ml. of acetic acid and14.5 g. selenium dioxide was refluxed for 2 hours. The mixture wasfiltered and the filtrate was made basic. An oil separated whichcrystallized on standing and was collected. Recrystallization from amixture of methylene chloride and petroleum ether gave off-whiteplatelets melting at 9091.Ultraviolet maxima (2-propanol) at 221 mp. (e21,600), 258 my. (5 12,400) and 292 my. (e 17,000); infrared absorption(CHCI at 1660 cm and at 1700 cm- Anal. Calcd. for C -,H, O;,: C. 74.99;H, 5.03 Found: C. 75.27; H, 5.26

EXAMPLE 4 Preparation of 2-benzoyl-4-chlorobenzaldehyde A solution of9.3 g. of 5-chloro-2-hydroxymethylbenzhydrol in 50 ml. of acetic acidand 5.2 g. of selenium dioxide was refluxed for 3 hours. The mixture wasfiltered, cooled, poured on ice, made alkaline and extracted with ether.Concentration and addition of petroleum ether gave the product as prismswhich after recrystallization from a mixture of ether and petroleumether melted at 8284.Ultraviolet maxima (2- propanol) at 230 my. (619,500) and 257 my. (6 23,500); infrared absorption (CHC1 at 1675 cm and1705 cm" Anal. Calcd. for C H ClO C, 68.72; Found: C, 69.05;

EXAMPLE 5 Preparation of 2-(4-bromobenzoyl)-benzaldehyde To a stirredsolution of 8.2 g. oflithium aluminum hydride in 180 ml. oftetrahydrofuran was added 40 g. of 2-(4-bromobenzoyl)-benzoic acid inthe course of 30 minutes. The mixture, after being kept at 25 for 2hours, was cooled and 40 ml. ofa saturated sodium sulfate solution wasadded slowly. The mixture was filtered and the filtrate concentrated.The resulting oily residue was dissolved in 32 ml. of acetic acid and 96ml. of xylene. This solution was added to a mixture of 17.1 g. ofselenium dioxide in 60 ml. of acetic acid and 120 ml. of xylene andrefluxed for 17 hours. During this time about 22 ml. of an aqueous phasehad collected in a Dean Stark receiver. The solution was filtered,washed with sodium hydroxide and concentrated. Addition of petroleumether gave white prisms melting at l03-l09. Recrystallization from amixture of ether and petroleum ether raised the melting point to ll0l13. Ultraviolet inflexion (2-propanol) at 225 mp. (e 17,500) and maximumat 261 mp. (e 22,200); infrared absorption (CHCl at 1675 cm and 1705 cm.

Anal. Calcd. for C H,,BrO C. Found: C,

EXAMPLE 6 Preparation of 2,3-dihydro-5-phenyl-5H-imidazo[2,la]isoindolesulfate from 2-benzoylbenzaldehyde A solution of 21 g. ofo-benzoylbenzaldehyde in 250 ml. of toluene and 34 ml. ofethylenediamine was refluxed for 24 hours. During this time 11.5 ml. ofan aqueous phase was separated in a Dean Stark receiver. The reactionmixture was concentrated in vacuo to an orange oil which was dissolvedin ethyl acetate and washed twice with water. The solution was dried andconcentrated, dissolved in 200 ml. of ethyl acetate and a solution of5.3 ml. of concentrated sulfuric acid in ml. of ethanol was added. Acrystalline precipitate was collected which after recrystallization froma mixture of methanol and ethyl acetate gave white prisms melting at226229 dec. Ultraviolet maxima (2- propanol) at 240 mp. (e 15,000) and276 my. (6 5,4000); infrared absorption (KBr) 1660 cm.

Anal. Calcd. for C H N H SQ: C, 57.82; H, 4.85;

C, 57.61; H, 4.81, N, 8.73

Found:

l7 tained. Nmr peaks (DMSO) at 6 3.6-4.6 (4H, multiplet), at 8 6.13 (1H,singlet), at 8 7.3-7.9 (9H, mu lt i-. plet).

EXAMPLE 7 Preparation of 2,3-dihydro--phenyl-5H-imidazo[2,1- a]isoindolesulfate 1 from 2-(2-aminoethyl)-3- phenylphthalimidine A solution of 1.2ml. of titanium tetrachloride in 30 ml. of xylene was added at 25 to astirred solution of 2.5 g. of 2-(2-aminoethyl)-3-phenylphthalimidine in150 ml. of xylene. The mixture was refluxed for 18 hours, cooled andwashed with an aqueous solution of sodium Carbonate. The xylene solutionwas extracted with 2N hydrochloric acid. The acidic extract was pouredon ice and made alkaline with sodium hydroxide. The solution wasextracted with ethyl acetate and the extract was concentrated. Additionof a solution of sulfuric acid in a mixture of ethanol andtetrahydrofuran and further dilution with ethyl acetate gave acrystalline precipitate. Recrystallization from a mixture of methanoland ethyl acetate gave the product as white prisms melting at 225228dec.

EXAMPLE 8 Preparation of 2,3-dihydro-5-hydroperoxy-5-phenyl- SH-imidazol2,1-a]isoindole The base liberated from 16.6 g. of 2,3-dihydro-5-pheny1-5H-imidazo[2,l-a]isoindole sulfate was dissolved in 50 ml. ofethanol and 11 ml. of a 30 percent by weight aqueous solution ofhydrogen peroxide was added. The mixture was stirred at 25 for 40 hours.A crystalline crop was collected and placed on a column containing 250g. of silica gel. Elution with a mixture of 1 part of methanol (volume)and 1 part of chloroform (volume) gave fractions from which onconcentration a crystalline residue was obtained. Recrystallization froma mixture of methanol and chloroform gave the product as white prismsmelting at 167-168 dec. Ultraviolet inflexions (Z-propanol) at 232 mp.(e 14.000) and 290 mp. (e= 2600), maxima at 269 mp. (e 4000) and 275 mp.(e 4400), infrared absorption (KBr) at 1665 cm.

Anal. Calcd. for C H N O C. 72.16; H. 5.30;

Found:

Anal. Calcd. for c,..H N,o .Hc1. c. saw 11 499; Found: c, 63.63; 11,4.83;

EXAMPLE 9.,

Preparation of S-(p-chlorophenyl)-2,3-dihydro-5-.

18 hydroperoxy-5l-l-imidazo[2,1-a]isoindole ride 1 Gram of2-(p-chlorobenzoyl)-benzaldehyde was thoroughly mixed with 0.9 g. ofethylenediamine toluene sulfonate and heated in a metal bath (bathtemperature, 125) for 1 minute. On cooling a deep yellow glassy materialwas obtained which on addition of methylene chloride, ethyl acetate andpetroleum ether gave a crystalline precipitate which was treated withice cold aqueous sodium hydroxide. The mixture was extracted with etherand the extract was exposed to air at 25 for 18 hours. A crystallinecrop was collected and suspended in methylene chloride. Addition ofethereal hydrogen chloride gave a crystalline material which afterrecrystallization from a mixture of methanol and ether gave white prismsmelting at -177 dec. Ultraviolet inflexion (2-propanol) at 223 mp. (e21,800) and 279 mu (6 5600), maximum at 243 mp. (e 15,500); infraredabsorption (KBr) at 1670 cm.

hydrochlo- Anal. Calcd. for C,,,H,;,ClN-;O .HCl: C. 56.99; H. 4.18;

Cl. 21.03. N. 8.31

To a suspension of 8.5 g. of 2,3-dihydro-5-phenyl-5H-imidazo[2,l-a]isoindole sulfate in water was added 50 ml. of 1Naqueous sodium hydroxide. Extraction with methylene chloride andconcentration gave an orange oil which was dissolved in a mixture of 30ml. of methylene chloride and 30 ml. of ethanol. To this solution wasadded 2.3 ml. of 30 percent by weight hydrogen peroxide. After stirringat 25 for 18 hours, a precipitate was collected which afterrecrystallization from methanol gave white prisms melting at 194196 dec.Ultraviolet inflexions (2-propanol) at 225 mp (6 15,500) and 290 mu (52250), maxima at 269 mp. (e 4100) and 276 mp. (e 4250); infraredabsorption (KBr) 1660 cm".

The 2-(2-benzoylphenyl)-2-imidazoline prepared in this manner can formthe isomeric 2,3-dihydro-5- hydroxy-S-phenyl-SH-imidazo[2,1-a]isoindole.

The hydrochloride was prepared by adding a solution of hydrogen chloridein methanol to a suspension of 2- (2-benzoylphenyl)-2-imidazoline inmethanol. Ether was added and the crystalline precipitate was collected.Recrystallization from a mixture of methanol and ether gave white prismsmelting at l73-l 76 dec. Ultraviolet maximum (2-propanol) at 252 mp. (e13,600); infrared absorption (KBr) at 1665 cm.

Anal. Calcd. for Cl H1 N O.HCl: Cl, 12.36 Found: Cl, 12.22

The hydrobromide was prepared by adding an aqueous solution ofhydrobromic acid to a suspension of 2 (2-benzoylphenyl)-2-imidazoline inethanol. Addition of ether gave a precipitate which afterrecrystallization from a mixture of ethanol and ether gave whiteplatelets melting at l93l94 dec.

Anal. Calcd. for cmH N OHBrz Br. 24.13 Found: Br. 24.15

EXAMPLE 11 Preparation of 2-(2-benzoylphenyl)-2-imidazoline from2,3-dihydro--hydroperoxy-5-phenyl-5H- imidazo[2, l -a]isoindole Asolution of 0.7 g. of sodium sulfite heptahydrate in 3 ml. of water wasadded to 0.5 g. of 2.3-dihydro-5-hydroperoxy-S-phenyl-SH-imidazo[2,l-a]isoind01e in 7 ml. ofdimethylformamide. The solution was heated to 100 for minutes. Oncooling and addition of ml. of water, 2-(2-benzoylphenyl)-2-imidazolinewas obtained.

EXAMPLE 1.2

Preparation of 2-(2-benzoylphenyl)-2-imidazoline from 2,3-dihydro-5-hydroperoxy-5-phenyl-5H imidazo 2, l -a]isoindole A solution of 0.1 g.of 2,3-dihydro-5-hydroperozy-5- phenyl-5H-imidazol2,l-a]isoindole and0.33 g. of triethylphosphite in 20 ml. of ethanol was kept on a steambath for 5 minutes, then 18 hours at The solution was concentrated invacuo and on addition of water 2- (2-benzoylphenyl)-2-imidazoline wasobtained.

EXAMPLE 13 EXAMPLE 14 Preparation of2-(2-aminoethyl)-l-phenylisoindoline A solution of 127 g. (0.59 mole) of2-hydroxymethylbenzhydrol was dissolved in 900 ml. of benzene, 80 g. ofanhydrous magnesium sulfate was added and the mixture was cooled in anice bath. Hydrogen bromide was bubbled into the stirred solution untilsaturation which took about minutes. During this time the temperature ofthe solution was kept at l5l8. The ice bath was removed and thetemperature was allowed to rise to in the course of 1 hour. The mixturewas heated for another hour at -45 on a steam bath. During the wholetime hydrogen bromide was passed into the solution to keep it saturated.The mixture was filtered and the solution was concentrated in vacuo togive a red oil which was dissolved in 200 ml. of benzene ture wasstirred and cooled to maintain a temperature of ca. 40 The mixture wasstirred at 25 for minutes. Two layers were obtained and separated. Thebenzene layer was washed with water and concentrated in vacuo. Theresidual oil was dissolved in 250 ml. of ether. This solution wasextracted twice with 300 ml. of cold 1N hydrochloric acid. The acidicaqueous phase was made alkaline with aqueous sodium hydroxide andextracted with 350 ml. of ether. The ethereal solution was washed with250 ml. of water, dried and concentrated. The residue was an amber oilwhich crystallized on scratching. This material melted up to ca. 45.

By analogy there were also prepared the following:

2-(3-aminopropyl)-l-phenylisoindoline2-(2-aminoethyl)-6-chloro-1-phenylisoindoline 2-( 2-aminoethyl lp-methoxyphenyl )isoindoline 2-( 4-aminobutyl 1 -phenylisoindoline 2-(2-amino-2-methylpropyl l -phenylisoindoline 2-( Z-aminopropyl 1-phenylisoindoline 2-(2-aminoethyl)-l-(p-hydroxyphenyl)isoindoline.

EXAMPLE 15 Preparation of 2-[2-(4-chlorobenzoyl)phenyl]-2- imidazolineTo 1 ml. of ethylenediamine was added 1 g. of2-(pchlorobenzoyl)-benzaldehyde in small portions. An exothermicreaction took place and after 5 minutes the reaction mixture was pouredinto ice water. A yellow solid precipitate was collected and dissolvedin methylene chloride. Ether and petroleum ether were added and thesolution was shaken in air at 25. A crystalline precipitate was obtainedwhich after recrystallization from a mixture of methylene chloride andmethanol gave white needles melting at l78-180 dec. Ultraviolet maxima(2-propanol) at 223 my. (6 21,250), 268 my. (5 4300), 275 my. (6 4320),inflexion at 290 my. (e 2200); infrared absorption (KBr) at 1660 cm.

Anal. Calcd. for C H CIN O: C, 67.49; H.

Found: C, 67.38; H

The 2 [2'-(4-chlorobenzoyl)phenyl]-2-imidazo1ine prepared in this mannercan form the isomeric 5-(4- chlorophenyl)-2,3-dihydro-5-hydroxy-5H-imidazo[2 l -a]isoindole.

The hydrochloride was prepared by adding a solution of hydrogen chloridein ether to a suspension of 5-(4-chlorophenyl)-2,3-dihydro-5-hydroxy-5H- imidazo[2,l-a]isoindole. Afterstirring for 30 minutes a crystalline crop was collected andrecrystallized from a mixture of chloroform and ether to give whiteprisms melting at l68-l7 l dec. Ultraviolet inflexion (2- propanol) at220 my. (6 22,000), maxima at 252 my. (e= 12,900), 226 mp. (e 13,000):infrared absorption (KBr) at 1670 cm".

Anal. Calcd. for C l-l ClN Ql-lClz Cl, 22.08 Found: C1, 22.18

EXAMPLE 16 Preparation of 2-[2-(4-anisoy1)phenyl]-2-imidazoline To 4 ml.of ethylenediamine was added 2 g. of 2-(panisoyl)-benza1dehyde in smallportions. The solution was stirred for minutes, poured into ice waterand extracted with methylene chloride. The methylene chloride solutionwas concentrated, the residue was dissolved in ethanol and a stream ofair was passed through the solution for 18 hours. A crystallineprecipitate was collected and after recrystallization from a mixture ofchloroform and ether gave white prisms melting at 17l-l74 dec.Ultraviolet maxima (2- propanol) at 227 mp. (e= 20,200), 277 mp (e=8800), 282 mp. (e 8750), inflexion at 292 mp. (e 7200); infraredabsorption (KBr) at 1660 cm.

Anal. Calcd. for C H N O C, 72.84; 73. 1

Found: C, 07 H,

EXAMPLE 17 Preparation of 2-[4'-chloro-2'-benzoy1phenyl]-2- imidazolineTo 2 ml. of ethylenediamine was added 0.9 g. of 2-benzoyl-4-chlorobenzaldehyde in small portions. The solution was stirredfor 10 minutes, poured into ice water and the solid yellow precipitatewas collected. This solid was dissolved in ether and shaken in air for45 minutes. A white precipitate was obtained which afterrecrystallization from a mixture of methylene chloride and methanolmelted at 200-202 dec. Ultraviolet maxima (2-propanol) at 242 mp (e17,500), 278 mp. (e 3800), 286 mp (e 3300), inflexions at 270 mp (e3450), 295 mp (e 2400); infrared absorption (KBr) at 1665 cm".

Anal. Calcd. for c,,,|-l,,.c|N o: C, 67.49; H,

Found: C, 67.42;

The 2-[4'-chloro-2-benzoy1phenyl]-2-imidazoline prepared in this mannercan form the isomeric 7- ch1oro-2,3-dihydro-5-hydroxy-5-pheny1-5H-imidazo[2, l -a]isoindole.

EXAMPLE 18 Preparation of 2-[2-(4-bromobenzoyl)phenyl]-2- imidazoline Asolution of 6 g. of 2-(4-bromobenzoyl)- benzaldehyde and 6.6 ml. ofethylenediamine in 50 ml. of toluene was refluxed for 18 hours. Duringthis time 0.5 ml. of an aqueous phase had separated in a Dean Starkreceiver. The mixture was concentrated in vacuo and the residual orangeoil was dissolved in a mixture containing ml. of ethanol, 15 ml. ofmethylene chloride and 1.5 ml. of a 30 percent by weight aqueoussolution of hydrogen peroxide. After stirring at for 18 hours a whiteprecipitate was collected which after recrystallization from methanolgave white needles melting at l87-189 dec. Ultraviolet maxima(2-propanol) at 227 mp. (e 22,800), 259 mp. (e 4700), 275 mp (e 4800),inflexion at 292 mp (e 2300); infrared absorption (KBr) at 1660 cm".

Anal. Calcd. for C H BrN- O: C, 58.3 Found: C, 58.2

The 2-[2-(4-bromobenzoy1)phenyl]-2-imidazo1ine prepared in this mannercan form the isomeric 5-(4- bromophenyl)-2,3-dihydro-5-hydroxy-5H-imidazo[2,1-a]isoind0le.

The hydrochloride was prepared by adding ethereal hydrogen chloride to asolution of 5-(4-bromophenyl)-2,3-dihydro-5-hydroxy-5H-imidazo[2,l-a]isoindole in a mixture ofmethylene chloride and methanol. The precipitate ws recrystallized froma mixture of ethanol and ether to give white prisms melting at l55-l58dec. Ultraviolet inflexion (2-propanol) at 223 mp. (e 20,000), maxima at251 mp (e 12,200) and 271 mp. (e 13,300); infrared absorption (KBr) at1660 cm.

Anal. Calcd. for C H BrN QHClz Cl. 9.70 Found: Cl, 9.82

EXAMPLE 19 Preparation of 2,3-dihydro-5-methoxy-5-phenyl-5H- imidazo[2,l-a]isoindole hydrochloride A solution of 5 g. of 2-(2-benzoylphenyl)-2-imidazoline in 50 ml. of methanol was refluxed for 18 hours. Thesolution was concentrated in vacuo, dissolved in 20 ml. of methanol and60 ml. of ether was added. Crystals precipitated and were identified asstarting material. The mother liquor was concentrated and the residuewas recrystallized from a mixture of methanol, methylene chloride andether to give the product as white prisms melting at l39-141 dec.Ultraviolet maxima (2-propanol) at 244 mp. (e 14,400) and 278 mp (e5100); infrared absorption (KBr) at 1670 cm".

C, 67.83; H, 5.70; OCH 10.32 Found: C, 67.84; H, 5.61;

OCH 10.44

Anal. Calcd. for C H N QHCI:

EXAMPLE 20 Preparation of 2 ,3 ,4,6-tetrahydro-6- phenylpyrimido[ 2,l-a]isoindole sulfate A solution of 10.5 g. of 2-benzoylbenzaldehyde and22 ml. of propylenediamine in 125 m1. of toluene was refluxed for 18hours. During this tie time ml. of an aqueous phase had separated in aDean Stark reeiver. The solution was concentrated in vacuo and theresidue was recrystallized from a mixture of ethanol and petroleum etherto give white prisms melting at l70-172 dec. Ultraviolet maximum(2-propanol) at 238 my. (6 18,200), inflexions at 246 my. (e =16,000),265 mu (6 5600), 276 mp. (e 3400) and 285 mu (6 2100); infraredabsorption (KBr) at 1675 cm.

Anal. Calcd. for C,;H ,N:.H-,SO,: C. 58.94; H, 5.24 Found: C, 58.62, H,5.49

EXAMPLE 21 Preparation of 2,3,4,5-tetrahydro-7-hydroxy-7-phenyl-7H-diazepino[2,1-a]isoindole A solution of 10.5 g. ofZ-benzoylbenzaldehyde and 28.5 ml. of 1,4-diaminobutane in 100 ml. oftoluene was refluxed for 18 hours. During this time 2.5 ml. of anaqueous phase had separated in a Dean Stark receiver. The solution wasexposed to air for 60 hours, concentrated and diluted with 300 ml. ofcarbon tetrachloride. A crystalline precipitate was obtained which wassuspended in 40 ml. of ethanol. A solution of 1.9 g. of oxalic acid in40 ml. of methanol was added and the solution was concentrated anddiluted with ether. The precipitate was collected and recrystallizedfrom a mixture of methanol and ether to give the oxalic acid salt aswhite prisms melting at ca. 200 dec. This salt was suspended in amixture of aqueous sodium carbonate solution and methylene chloride. Themethylene chloride solution was concentrated and the residue wasrecrystallized from a mixture of chloroform and ether to give theproduce as white needles melting at 216-220 dec. Ultraviolet maxima(2-propanol) at 258m (6 5000), 265 mp. (e 5100), 273 mp. (e 4800),inflexions at 230 mu (6 15,000), 290 my. (6 2400); infrared absorption(KBr) at 1650 cm.

phenylphthalimidine A solution of g. (0.1 mole) of l,2,3,9b-tetrahydro-9b-phenyl-5H-imidazo[2,l-a]isoindol-5-one in 150 ml. of acetic acidcontaining 2.5 g. of hydrogen chloride was shaken under one atmosphereof hydrogen at 25 using 0.5 g. of platinum oxide as catalyst. 1n thecourse of 7 hours, 3000 ml. of hydrogen (theory ca. 2500 ml.) wasabsorbed and the rate of uptake had slowed down considerably. Thesolution was poured into ice water, basified with ammonia and extractedwith methylene chloride. The organic phase was dried and concentrated.The residue crystallized with ether and after recrystallization from amixture of methylene chloride and petroleum ether gave white prisms of2-( 2- aminoethyl)-3-phenylphtha1imidine melting at 9093.

'YFOCHH Cm la n|u.r i 6 279 mu, 5 1900.

To 250 ml. of concentrated sulfuric acid was added, with stirring andslight cooling, 37.5 g. (0.545 mole) of sodium nitrite. To this wasadded 120.5 g. (0.50 mole) of 2-(2-aminobenzoyl)benzoic acid at such arate that the temperature of the reaction mixture remained between 3040.After the addition was complete the reaction mixture was stirred for 1hour and then poured into 1 liter of ice and water and filtered. Thefiltrate was added rapidly to a stirred solution of 55 g. (0.555 mole)of cuprous chloride, 150 g. of sodium chloride, 250 ml. of concentratedhydrochloric acid and 300 ml. of water. The precipitated gum wasextracted with chloroform and the extracts were washed twice with water,dried over anhydrous sodium sulfate and evapo rated under vacuo to leavea red oil which crystallized upon scratching. Recrystallization from 200ml. of ethyl acetate gave 2-(2-chlorobenzoyl)benzoic acid as a pinksolid. A sample recrystallized three times from ethyl acetate gavecolorless prisms, double m.p. l12l 16 and 124126.

To a stirred suspension of 22.8 g. (0.60 mole) of lithium aluminumhydride in 700 m1. of dry tetrahydrofuran was added 104 g. (0.40 mole)of 2-(2- chlorobenzoyl)benzoic acid prepared as above in portionskeeping the reaction mixture temperature between l5-30 with ice cooling.After the addition was complete the reaction mixture was stirred for 1hour. Ether (400 ml.) was added followed by the slow addition of ml. ofwater, with ice cooling. The mixture was filtered through a largesintered glass funnel which contained a matting of Celite filter-aid.The filtered solids were washed with tetrahydrofuran and the combinedfiltrates were evaporated under vacuo to a yellow oil which crystallizedupon scratching. The-material was recrystallized from 150 ml. ofisopropyl ether to give 2-chloro-2-hydroxymethylbenzhydrol as a slightlypink solid, mp 87. A sample was recrystallized three times fromisopropyl ether to give colorless prisms, m.p. 86-87.

A 2-liter, 3-necked, round bottomed flask was fitted with a mechanicalstirrer, dropping funnel and a Dean- Stark trap fitted with a condenser.A mixture of 41.7 g. (0.376 mole) of selenium dioxide in ml. of aceticacid and 300 ml. of xylene was refluxed for 15 minutes. To the boilingmixture was added dropwise during one hour, a solution of 74.4 g. (0.3mole) of 2-chloro-2- hydroxymethylbenzhydrol prepared as above in 85 m1.of acetic acid and 250 ml. of xylene. The Dean-Stark trap was cooledduring this time to promote separation of an aqueous phase. About 60 ml.of aqueous phase was separated during 5 hours. The reaction mixture wasrefluxed for a total of 22 hours, cooled and filtered.

The filtrate was added to 800 ml. of ice and water, I

made alkaline with 50 percent sodium hydroxide and the mixture extractedwith 600 ml of ether. The extracts were washed with water, dried overanhydrous sodium sulfate and evaporated to yield an orange oil whichcould not be crystallized. Vapor phase chromatographic analysis showedthe presence of two compounds. a

45.4 Grams of the oil, 52.5 g. (0.875 mole) of ethylenediamine and 400ml. of benzene were refluxed for hours in a round bottomed flaskequipped with a Dean-Stark trap and a condenser. About 6 ml. of aqueousphase separated in the trap. The reaction mixture was cooled, washedthree times with saturated aqueous salt solution and dried overanhydrous sodium sulfate. Air was then bubbled through the benzenesolution for hours but only a small amount of solid separated.

The benzene was removed under vacuo and the residue was dissolved in 150ml. of ethanol and 40 ml. (0.350 mole) of 30 percent hydrogen peroxide.After stirring for 3 hours the ethanol was removed under vacuo and 300ml. of benzene was added to the residue. The aqueous phase was separatedand the benzene solution was dried over anhydrous sodium sulfate andevaporated under vacuo to leave a pale yellow oil. Ether (150 ml.) wasadded and a crystalline solid separated. The mixture was filtered togive a pale yellow solid, mp. 164l 67 dec. The ether filtrate wasstirred at room temperature, exposed to air, for two days. Theprecipitated solid was filtered to give an additional pale yellow solid.Thin layer chromatography of the combined solids showed the presence ofone majorcomponent, Rf 0.41, and a minor component, Rf 0.67. The lattercomponent was2,3-dihydro-5hydroperoxy5-(ochlorophenyl)-5Himidazo[2,l-a]isoindolesince the yellow solid precipitated iodine from a saturated methanolicpotassium iodide solution.

To a suspension of the yellow solid in 60 ml. of re fluxing methanol wasadded a solution of 4.28 g. (0.017 mole) of Na SO '7H O in 30 ml. ofwater over a period of 5 minutes. After refluxing for 15 minutes longerthe reaction mixture was cooled and filtered. The filtered solid waswashed 3 times with ml. of water and dried. Recrystallization frommethanol-chloroform gave 2-[2-(2-chlorobenzoyl)phenyll-IZ-imidazoline ascolorless prisms, m.p. l80l8l dec.

Anal. Calcd. for CmHlflClNgO: C. 67.49; H. 4.60;

Found: C, 67.15; H. 4.56;

The 2-[2-(2-chlorobenzoyl)phenyl]-2-imidazoline prepared in this mannercan form the isomeric 2,3- dihydro-S-hydroxy-S-(Z-chlorophenyl)-5H-imidazo[2,l-a]isoindole.

To a hot solution of 6.0 g. (21.2 mmoles) of 2-[2-(2-chlorobenzoyl)phenyl]-2-imidazoline in ml. of 6 N methanolic hydrogenchloride and 35 ml. of methanol was added 200 ml. ofether and thesolution cooled. Filtration gave 2-[ 2-( 2-chlorobenzoyl)phenyl ]-2-imidazoline hydrochloride, m.p. l78180 dec. Dilution of the motherliquors with 200 ml. of ether followed by cooling and filtering affordedan additional quantiity of hydrochloride. Recrystallization frommethanol-ether gave colorless prisms, m.p. l78-180 dec.

Anal. Calcd. for C H CI N O: Cl, 2

Found: Cl, 2

EXAMPLE 24 Preparation of 2-(Z-benzoylphenyl)-2-imidazoline via 1,2,3,9b-tetrahydro-Sl-Hmidazol 2, 1 -a]isoindol-5-one A solution of 7.5 g.of phthalaldehydic acid in 30 ml. of ethanol and 34 ml. ofethylenediamine was refluxed for 16 hours. The solution was concentratedin vacuo and the residue was dissolved in methylene chloride. Thesolution was washed with water, dried and concentrated. The residue wasdistilled in a bulb tube at 0.3 mm at a bath temperature of l50-l Acolorless oil was obtained which was dissolved in methanol and onaddition of ethereal hydrogen chloride gave white prisms ofl,2,3,9b-tetrahydro-5H-imidazo[2,la]isoindol-5-one hydrochloride, m.p.222224 dec.

The salt obtained in the preceding experiment was treated with aqueouspotassium carbonate solution. Extraction with methylene chloride gave anoil of which 0.9 g. was dissolved in a mixture of 25 ml. of benzene and10 ml. of ether. To this solution was added 5.5 ml. of a 2 N solution ofphenyl lithium in a mixture of benzene and ether (7:3). After stirringat 25 for 1 hour the solution was poured into ice water and extractedwith ethyl acetate. This solution was concentrated and the residue wasexposed to air for 48 hours. On addition of methylene chloride crystalswere obtained which were dissolved in methanol. Addition of etherealhydrochloric acid gave white prisms which after recrystallization from amixture of methanol and ether gave crystals melting at l73-l75 dec. Thismaterial was identical with authentic 2-(2-benzoylphenyl)-2imidazolinehydrochloride.

We claim:

1. A compound of the formula:

wherein R,, R R and R are each independently selected from the groupconsisting of hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, andtrifluoromethy].

2. The compound according to claim 1 wherein each of R R R and R arehydrogen, i.e., the compound 2-benzoylbenzaldehyde.

3. The compound according to claim 1 wherein R R and R are each hydrogenand R is chloro and is in pposition, i.e., the compound2-(p-chlorobenzoyl)- benzaldehyde.

. 4. The compound according to claim 1 wherein R R and R are eachhydrogen and R is methoxy and is in p-position, i.e., the compound2-(panisoyl)benzaldehyde.

5. The compound according to claim 1 wherein R R and R are each hydrogenand R is chloro and is in 4-position, i.e., the compound 2-benzoyl-4-chlorobenaldehyde.

6. The compound according to claim 1 wherein R R and R are each hydrogenand R is bromo and is compound 2-(p- UNITED STATES PATENT OFFICECERTIFICATE OF CORRECTION PATENT NO. I 3,875,238 DATED April 1, 1975INVENTOR(S) Werner Metlesics & Leo Henryk Sternbach It is certified thaterror appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

Column 27 claim 5, line 6, "chlorobenaldehyde" should be:

chlorobenzaldehxde Column 28 claim 6, line 2, "benaldehyde" should be:

benzaldehyde Signed and Scaled this fourth Day Of No vember19 75 [SEAL]A ttest:

RUTH C. MASON v C. MARSHALL DANN Arresting Officer Commissioner ofParents and Trademarks

1. A COMPOUND OF THE FORMULA:
 2. The compound according to claim 1wherein each of R1, R2, R3, and R4 are hydrogen, i.e., the compound2-benzoylbenzaldehyde.
 3. The compound according to claim 1 wherein R1,R2, and R3 are each hydrogen and R4 is chloro and is in p-position,i.e., the compound 2-(p-chlorobenzoyl)benzaldehyde.
 4. The compoundaccording to claim 1 wherein R1, R2, and R3 are each hydrogen and R4 ismethoxy and is in p-position, i.e., the compound2-(p-anisoyl)benzaldehyde.
 5. The compound according to claim 1 whereinR1, R3, and R4 are each hydrogen and R2 is chloro and is in 4-position,i.e., the compound 2-benzoyl-4-chlorobenaldehyde.
 6. The compoundaccording to claim 1 wherein R1, R2, and R3 are each hydrogen and R4 isbromo and is in p-position, i.e., the compound2-(p-bromobenzoyl)benaldehyde.
 7. The compound according to claim 1wherein R1, R2, and R3 are each hydrogen and R4 is chloro and is ino-position, i.e., the compound 2-(o-chlorobenzoyl)benzaldehyde.